Project Summary The long-term goal of this research is to elucidate neuronal mechanisms that allow the brain to recover consciousness and cognition after anesthesia. Some patients recover consciousness prematurely during surgery. Intraoperative awareness is associated with a significant risk of post-traumatic stress disorder. Others conversely, do not recover cognitive function long after anesthetics have been discontinued. Delayed recovery is associated with higher morbidity, longer hospital stays, and increased healthcare costs. While brain activity monitors have been used for decades to mitigate these peri-anesthetic complications, current monitors of brain activity are inadequate. Anesthetic awareness cannot be reliably detected or prevented and delayed recovery of cognition affects a large fraction of patients who undergo anesthesia. All existing brain activity monitors assume that depth of anesthesia is a continuous one-dimensional measure closely tied to the anesthetic concentration. In contrast, we show that during recovery of consciousness after isoflurane thalamocortical system abruptly transitions among a small number of discrete activity patterns. Transitions among discrete activity patterns persist even when anesthetic concentration is fixed. While many such transitions occur during recovery, all paths towards wakefulness funnel through a small subset of discrete activity patterns. Our central hypothesis is that: Transitions among a small number of discrete activity patterns is a universal feature of recovery from anesthesia and that directed disturbances of such transitions delay or accelerate recovery. In Aim 1 we will directly record neuronal activity in the cortex and thalamus during recovery from different anesthetics. We will detect and quantify transitions among discrete activity patterns using robust statistical methodology developed and validated recently in our lab. In Aims 2 and 3 we will use a combination of direct recordings of neuronal activity and precise optogenetic perturbations to determine the role of orexinergic and noradrenergic neuronal pathways in mediating transitions between different discrete activity patterns. We hypothesize that by manipulating these arousal pathways will be able to either accelerate or conversely impede recovery. This contribution is significant because we propose to provide an unprecedented ability to monitor and influence the anesthetic state. In the short term, this work may lead to the development of robust means of monitoring brain activity under anesthesia. In the long run, identification of neuronal mechanisms responsible for transitions among discrete activity patterns may lead to the development of targeted therapies for preventing unintended awareness and accelerating recovery after anesthesia. The proposed research is innovative because by focusing on mechanisms underlying abrupt transitions between discrete activity patterns we will identify previously unknown neuronal processes that sculpt the recovery of consciousness after anesthesia.